US20230226018A1 - Application of compound using intra-cyclic peroxo-bridged sesquiterpenes as parent nucleus in metabolism-related fatty liver diseases - Google Patents

Application of compound using intra-cyclic peroxo-bridged sesquiterpenes as parent nucleus in metabolism-related fatty liver diseases Download PDF

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US20230226018A1
US20230226018A1 US18/011,198 US202118011198A US2023226018A1 US 20230226018 A1 US20230226018 A1 US 20230226018A1 US 202118011198 A US202118011198 A US 202118011198A US 2023226018 A1 US2023226018 A1 US 2023226018A1
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compound
liver
metabolism
sesquiterpenes
peroxo
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Yuliang Wang
Kexuan Tang
Jiangao FAN
Jing Zeng
Xiaofen SUN
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SUZHOU TANGJI BIOTECHNOLOGY Co Ltd
Shanghai Jiaotong University
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SUZHOU TANGJI BIOTECHNOLOGY Co Ltd
Shanghai Jiaotong University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of drugs for the treatment of liver diseases, in particular, to an application of a compound using intra-cyclic peroxo-bridged sesquiterpenes as a parent nucleus in metabolism-related fatty liver diseases.
  • Artemisinin compounds as the most remarkable ones among all compounds with intra-cyclic peroxo-bridged sesquiterpenes in terms of medical application, are currently the first-line drugs for the treatment of malaria.
  • many studies have focused on the new efficacy of artemisinin compounds, involving the treatment of tumors, inflammation, asthma, skin diseases, lupus erythematosus, and other diseases.
  • lupus erythematosus which has entered the clinical research stage, most new indications only remain in the description of a. phenomenon, and no new indication has been approved for clinical application. The reason is that the above studies mainly focus on pharmacological phenomena and lack mechanisms of action, so it is difficult to find the disease classification for which various compounds are most suitable, and thus the compounds fail to show better effects than the existing drugs.
  • Precision drug therapy is a category of precision medicine.
  • Precision medicine encompasses precision diagnosis, precision treatment (including precision drug therapy), precision prevention, and the like, and the core concept of precision medicine is to formulate reliable disease prevention and treatment regimens and implement corresponding medical behaviors based on objective and effective indicators and evidence.
  • Traditional clinical treatment focuses on the correlation between empirical evidence, such as medical history and subjective examination, and clinical presentation as well as treatment outcome.
  • traditional clinical treatment pays attention to the group effect and statistical effect, leading to the domination of the concept of group medicine, such as “grouping” and “standardization”.
  • Precision medicine is a personalized medical model where treatment regimens are formulated according to the individual characteristics of patients. The word “precision” is reflected in the precise determination of the causes of individual diseases in combination with precise drug treatment with a. clear mechanism of action.
  • the present invention aims to solve the current difficulties in the new application of artemisinin drugs and creatively verify its new application in lipid metabolism-related fatty liver diseases, especially the new application in fatty liver diseases caused by mitochondrial dysfunction and decreased fatty acid 1-oxidation capacity.
  • the present invention discloses an application of a compound using infra-cyclic peroxo-bridged sesquiterpenes as a parent nucleus in metabolism-related fatty liver diseases.
  • the compound using intra-cyclic peroxo-bridged sesquiterpenes as the parent nucleus has the structure shown in Formula I:
  • A denotes O, —OH, —OCH 3 , —OCH 2 CH 3 , or —OC 4 H 5 O 3
  • the compound using intra-cyclic peroxo-bridged sesquiterpenes as the parent nucleus is configured for preparing a drug or a composition for treating metabolism-related fatty liver diseases.
  • the compound using intra-cyclic peroxo-bridged sesquiterpenes as the parent nucleus is artemisinin, dihydroartemisinin, artemether, or arteether, respectively.
  • the chemical structural formulas of artemisinin, artesunate, dihydroartemisinin, artemether, and arteether are as follows:
  • the compound using intra-cyclic peroxo-bridged sesquiterpenes as the parent nucleus has the function of regulating mitochondria in liver cells.
  • the function of regulating mitochondria in liver cells is to enhance the fatty acid ⁇ -oxidation capacity of the mitochondria
  • metabolism-related fatty liver diseases include liver lesions caused by mitochondrial dysfunction and decreased fatty acid ⁇ -oxidation capacity.
  • liver lesions include liver steatosis, inflammation, and fibrosis.
  • the present invention also discloses a drug containing the compound with the structure shown in Formula I described above for the prevention or treatment of fatty liver diseases.
  • compositions for the prevention or treatment of fatty liver diseases which contains the compound with the structure shown in Formula I described above or a pharmaceutically acceptable salt thereof as an active ingredient.
  • composition contains one or more carriers, excipients, or diluents that are pharmaceutically acceptable.
  • the present invention relates to the application of the compound with the structure shown in Formula I described above or a pharmaceutical salt thereof in the preparation of a product for the prevention or treatment of fatty liver diseases.
  • fatty liver diseases are liver lesions caused by mitochondrial dysfunction and decreased fatty acid ⁇ -oxidation capacity, and the liver lesions include liver steatosis, inflammation, and fibrosis.
  • the present invention has the following advantages: It is found and proven that a compound using intra-cyclic peroxo-bridged sesquiterpenes as a parent nucleus, in particular, a series of derivatives represented by artemisinin, can improve the function of mitochondria in liver cells and enhance the fatty acid ⁇ -oxidation capacity thereof, thereby adapting to the treatment of metabolic dysfunction caused by mitochondrial dysfunction, as well as the resulting liver fat accumulation, inflammation, and fibrotic lesions.
  • FIG. 1 is a column chart of the content of triglyceride in HepG2 liver cancer cells of a control group, a model group, and an artesunate group.
  • FIGS. 2 A- 2 B are diagrams of Nile red staining of lipid droplets, where FIG. 2 A is the model group, and FIG. 2 B is the artesunate group.
  • FIG. 3 shows the mRNA expression results of CIDE series genes related to lipid droplets.
  • CIDE gene expression is related to the size of lipid droplets in cells. Artesunate can reduce the volume of lipid droplets in cells and the content of fatty acids by reducing CIDE gene expression.
  • *, **, and *** denote that there are significant differences. Among them, * denotes p ⁇ 0.05,** denotes p ⁇ 0.01,*** denotes p ⁇ 0.001, and **** denotes p ⁇ 0.0001.
  • FIG. 4 shows the effect of artesunate on the mRNA expression level of AMPK ⁇ .
  • Adenosine 5′-monophosphate (AMP)-dependent protein kinase is a key molecule in regulating bioenergy metabolism. Artesunate increases the expression of AMPK ⁇ , indicating that artesunate can activate intracellular energy metabolism and consume excess intracellular fatty acids.
  • FIG. 5 shows the effect of artesunate on the pathways of adenosine 5′-monophosphate-activated protein kinase (AMPK)-sterol regulatory element binding protein-1c (SREBP1c)-acetyl coA carboxylase (ACC)-stearoyl-coA desaturase-1 (SCDI)-fatty acid synthase (FAS).
  • SREBP1c-ACC/SCD1/FAS is a key upstream gene of intracellular lipid synthesis.
  • Artesunate can reduce the expression of the genes of the pathways, indicating that artesunate can inhibit lipid synthesis in cells and reduce the lipid content in cells.
  • FIG. 6 shows the effect of artesunate on the pathways of AMPK-cluster of differentiation 36 (CD36)-carnitine palmitoyltransferase 1 (CPT1).
  • the CPT1 gene is a key gene for fatty acids transported to mitochondria; artesunate increases the expression of CPT1, which can accelerate mitochondrial fatty acid oxidation and reduce the lipid content in cells.
  • FIG. 7 shows the effect of artesunate on the mRNA expressions of PPAR ⁇ and PPAR ⁇ .
  • Artesunate can significantly increase the mRNA expressions of PPAR ⁇ and PPAR ⁇ .
  • Peroxisome proliferator-activated receptor ⁇ PPAR ⁇
  • PPAR ⁇ Peroxisome proliferator-activated receptor ⁇
  • FIG. 8 shows pathological sections, stained with HE and Oil red O, respectively, of the livers of high-fat and high-sugar-induced mice. Artemisinin can inhibit liver steatosis induced by a high-fat and high-sugar diet.
  • FIGS. 9 A- 9 H show the effects of artemisinin on serum liver enzymes, lobular inflammation, and ballooning of liver cells.
  • FIG. 9 A shows the effect on liver index %.
  • FIG. 9 B shows the effect on liver steatosis.
  • FIG. 9 C shows the effect on inflammation.
  • FIG. 9 D shows the effect on ballooning.
  • FIG. 9 E shows the effect on alanine aminotransferase (ALT).
  • FIG. 9 F shows the effect on aspartate aminotransferase (AST).
  • FIG. 9 G shows the effect on tumor necrosis factor ⁇ (TNF ⁇ ).
  • FIG. 9 H shows the effect on interleukin 6 (IL-6).
  • FIGS. 9 A- 9 H shows the effect on FIGS. 9 A- 9 H , FIGS. 10 A- 10 I , and FIGS.
  • FIGS. 9 A- 9 H , FIGS. 10 A- 10 I , and FIGS. 11 A- 11 G * denotes p ⁇ 0.05, ** denotes p ⁇ 0.01, *** denotes p ⁇ 0.001, and **** denotes p ⁇ 0.0001.
  • FIGS. 10 A- 10 I show the expression levels of lipid metabolism-related genes in mice liver; artemisinin intervention can reduce the expression of lipid metabolism-related genes in mice liver, thereby reducing the synthesis of lipids in the liver.
  • FIGS. 11 A -11G show the expression of autophagy-related proteins in mice liver; artemisinin intervention can restore the level of mitophagy in mice to maintain the quantity and quality of mitochondria in mice liver at the optimal state and inhibit mitochondrial damage and liver lesions induced by high-fat and high-sugar.
  • LC3 represents autophagy microtubule-associated protein light chain 3
  • TOR represents the rapamycin target protein.
  • HepG2 liver cancer cells purchased from the Cell Bank of the Chinese Academy of Sciences. HepG2 liver cancer cells are widely used in pharmacological and toxicological studies. They can express many differentiated liver functions, such as plasma protein synthesis and secretion, cholesterol and triglyceride metabolism, lipoprotein metabolism and transport, bile acid synthesis, glycogen synthesis, or insulin signal transduction.
  • the addition of free fatty acid (FFA) in a medium can cause the accumulation of lipids in HepG2 liver cancer cells, damage the mitochondrial function, and reduce the fatty acid ⁇ -oxidation capacity, thereby resulting in the increase in the number and volume of lipid droplets.
  • FFA free fatty acid
  • FFA was not added to the medium of the control group, while FFA was added to the mediums of the model group and artesunate group.
  • the addition amount is shown in FIG. 1 .
  • the formation of large lipid droplets in the model group is an important marker of steatosis in liver cells.
  • HepG-2 liver cancer cells with passage times less than 20 times were selected and inoculated into a 12-well plate at a density of 3 ⁇ 10 5 cells/mL. Drug treatment was performed after inoculating for 24 h, and the cells were divided into 3 groups with 4 wells in each group.
  • a complete medium containing 1% bovine serum albumin (BSA) was used as the control group.
  • a complete medium containing 1% BSA and 1 mM/L FFA was used as the high-fat model group.
  • a complete medium containing 1% BSA, 1 mM/L FFA, and 5 ⁇ M/L, artesunate was used as the artesunate group.
  • Quantitative real-time PCR qRT-PCR was used to detect the expression of CIDE series genes.
  • CIDE Cell-Death-Inducing DNA-Fragmentation-Factor-Like Effector
  • CIDE series genes include the Cide-a gene, the Cide-b gene, and the Cide-c gene.
  • the expression. level of these genes is positively correlated with the size of lipid droplets.
  • the mRNA expression levels of the Cide-a gene, Cide-b gene, and Cide-c gene in the control group, model group, and artesunate group it was found that the mRNA expression of Cide-a gene and Cide-b gene in the artesunate group were significantly lower than those in the model group, as shown in FIG. 3 .
  • Artesunate can reduce the expression of CIDE series genes, suggesting that artesunate can reduce the size of lipid droplets by increasing fatty acid ⁇ -oxidation.
  • FIG. 3 shows, assuming the mRNA expression of CIDE series genes in the control group as 1, the relative mRNA expression in other groups compared with the control group.
  • Artesunate can act as an AMPK activator to some extent. Therefore, after artesunate treatment, the mRNA level of AMPK ⁇ (PRKAA1) in HepG2 cells in the artesunate group was significantly up-regulated compared with that in the model group (p ⁇ 0.01), as shown in FIG. 4 .
  • SREBP1c-ACC/SCD1/FAS are genes related to intracellular fatty acid synthesis; artesunate can reduce the expression of those genes related to the pathways, reduce the synthesis of fatty acids in cells, activate AMPK genes, and increase the fatty acid ⁇ -oxidation capacity in liver cells.
  • CPT-1 carnitine palmitoyl transferase 1
  • PPAR is a key gene affecting fatty acid ⁇ -oxidation, and the increase in the expression thereof indicates that the fatty acid ⁇ -oxidation is accelerated in cells.
  • mice were selected and fed with feedstuffs that were added with 10% lard and 5% fructose. After 12 weeks, the mice suffered from liver metabolism disruption, generated insulin resistance, and were stuck in mitochondrial dysfunction in liver cells, thus resulting in a decrease in fatty acid ⁇ -oxidation capacity and fat accumulation in the liver, and inflammation and fibrosis were produced. Artemisinin was given at a dosage of 100 mg/kg from the 13th week as a treatment for 12 weeks. At the end of the experiment, the mice were dissected to obtain livers.
  • liver steatosis activity fibrosis SAF scoring system.
  • SAF steatosis activity fibrosis
  • the results showed that there were obvious fat blebs in the mice's livers after high-fat induction, and large red areas were observed after the Oil red O staining.
  • the fat blebs and Oil red O staining areas in the livers of the mice treated with artemisinin were both closer to those of the mice in the normal group, indicating that artemisinin intervention could significantly improve liver steatosis induced by a high-fat diet, as shown in FIG. 8 .
  • RNA and protein were extracted, and the study of the expression of related genes and proteins was conducted to detect the expression levels of lipid metabolism-related genes in liver tissue.
  • the results showed that the upstream gene expression levels of genes related to lipid synthesis were inhibited in mice treated with artemisinin on the high-fat and high-sugar diet.
  • the results suggest that artemisinin can reduce the lipid content in the liver of mice induced by the high-fat and high-sugar diet by reducing the expression of genes related to lipid synthesis, as shown in FIGS. 10 A- 10 I .
  • the primer sequences of the genes are shown in Table 2.
  • Target of rapamycin is a key protein in the control of autophagy, which can sense various change signals of cells and strengthen or reduce the occurrence level of autophagy.
  • TOR rapamycin
  • the above studies on the expression of mice liver proteins revealed that TOR was abnormally activated in the liver of mice having a high-fat and high-sugar diet, and mitopha.gy was significantly inhibited.
  • the mice fed with a high-fat and high-sugar diet were subjected to the artemisinin intervention, the mice could effectively resist the mitochondrial dysfunction and the decrease in the autophagy level caused by the high-fat and high-sugar diet, thereby reducing steatosis and inflammation in the liver, as shown in FIGS. 11 A- 11 G .
  • LC3II/Actin is marked in FIG. 11 C , indicating that the expression level of LC3II protein in the control group (Con), high-fat group (HFD), and high-fat plus artemisinin group (HFD+ART) was homogenized by the ratio of the expression level of LC3II protein to that of the reference protein Actin.
  • mitochondria When mitochondria are senescent or dysfunctional, to maintain the normal operation of cells, on the one hand, the cells will clear the abnormal mitochondria through autophagy, and this mitochondrial clearance mechanism is also commonly defined as mitophagy.
  • mitochondria with abnormal function cannot be removed in time, that is, when the function of mitopha.gy is defective, a large number of mitochondrial free radicals derived from mitochondria will be produced, leading to inflammation.
  • the induction of high-fat and high-sugar can increase mitochondrial pressure levels, causing swelling and functional damage.
  • Mitophagy is the targeted phagocytosis and destruction of mitochondria. by cellular autophagy devices, which is generally considered to be the main mechanism of mitochondrial quality control.
  • Artemisinin treatment can restore the level of mitophagy in mice induced by a high-fat and high-sugar diet to maintain the quantity and quality of mitochondria in the liver of mice, restore the function of mitochondria, and inhibit the occurrence of liver fatty lesions and inflammation.

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CN1833644B (zh) * 2005-03-18 2010-07-21 中国人民解放军第三军医大学 青蒿素及其衍生物二氢青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯在制药中的应用
CN1903191A (zh) * 2005-07-29 2007-01-31 方步武 青蒿琥酯在制备抗肝纤维化制剂中的应用
CN102755316A (zh) * 2012-07-16 2012-10-31 中国科学院武汉病毒研究所 青蒿素及其衍生物在制备治疗丙型肝炎病毒药物中的应用
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CN103230392A (zh) * 2013-04-10 2013-08-07 上海交通大学 青蒿素类化合物在制备抗动脉粥样硬化药物中的用途
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